Identification of gene targets of mutant C/EBP[alpha] reveals a critical role for MSI2 in CEBPA-mutated AML
Mutations in the gene encoding the transcription factor CCAAT/enhancer-binding protein alpha (C/EBP[alpha]) occur in 10-15% of acute myeloid leukemia (AML). Frameshifts in the CEBPA N-terminus resulting in exclusive expression of a truncated p30 isoform represent the most prevalent type of CEBPA mut...
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Published in | Leukemia Vol. 35; no. 9; p. 2526 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Nature Publishing Group
01.09.2021
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Subjects | |
Online Access | Get full text |
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Summary: | Mutations in the gene encoding the transcription factor CCAAT/enhancer-binding protein alpha (C/EBP[alpha]) occur in 10-15% of acute myeloid leukemia (AML). Frameshifts in the CEBPA N-terminus resulting in exclusive expression of a truncated p30 isoform represent the most prevalent type of CEBPA mutations in AML. C/EBP[alpha] p30 interacts with the epigenetic machinery, but it is incompletely understood how p30-induced changes cause leukemogenesis. We hypothesized that critical effector genes in CEBPA-mutated AML are dependent on p30-mediated dysregulation of the epigenome. We mapped p30-associated regulatory elements (REs) by ATAC-seq and ChIP-seq in a myeloid progenitor cell model for p30-driven AML that enables inducible RNAi-mediated knockdown of p30. Concomitant p30-dependent changes in gene expression were measured by RNA-seq. Integrative analysis identified 117 p30-dependent REs associated with 33 strongly down-regulated genes upon p30-knockdown. CRISPR/Cas9-mediated mutational disruption of these genes revealed the RNA-binding protein MSI2 as a critical p30-target. MSI2 knockout in p30-driven murine AML cells and in the CEBPA-mutated human AML cell line KO-52 caused proliferation arrest and terminal myeloid differentiation, and delayed leukemia onset in vivo. In summary, this work presents a comprehensive dataset of p30-dependent effects on epigenetic regulation and gene expression and identifies MSI2 as an effector of the C/EBP[alpha] p30 oncoprotein. |
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ISSN: | 0887-6924 1476-5551 |
DOI: | 10.1038/s41375-021-01169-6 |